Bariatric Surgery Changes Metabolism and Genes

Weight loss following gastric bypass surgery was associated with changes in gene methylation that may affect insulin sensitivity, researchers said.

by John Gever John Gever Deputy Managing Editor, MedPage Today
April 11, 2013

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Weight loss following gastric surgery was associated with changes in gene methylation that may affect insulin sensitivity.

Note that methylation of two specific genes, PGC-1-alpha and PDK4, both of which help regulate mitochondrial activity and energy use in skeletal muscle, were abnormal in patients relative to controls at baseline, and were normalized with weight loss.

Weight loss following gastric bypass surgery was associated with changes in gene methylation that may affect insulin sensitivity, researchers said.

Whereas expression of 14 genes was abnormal prior to surgery because of different levels of DNA promoter methylation, compared with normal-weight patients, methylation status at 11 of the genes was normalized in the surgical patients when analyzed after weight loss had occurred, according to Juleen R. Zierath, PhD, of the Karolinska Institute in Stockholm.

"Dynamic changes in DNA methylation may be an early event that orchestrates metabolic gene transcription involved in the regulation of insulin sensitivity in human obesity," the researchers wrote.

Zierath and colleagues added that environmental factors may drive formation of what they called "the metabolic memory" of adult cells.

It has also been noted that bariatric surgery can induce rapid and durable remission of type 2 diabetes. The mechanisms, however, have remained obscure. Zierath and colleagues sought to determine whether the surgery and resultant weight loss may lead to epigenetic changes relevant to metabolic activity.

They performed a series of analyses on 14 obese patients (eight women and six men) before undergoing Roux-en-Y bypass surgery and again 6 months later, as well as on 16 normal-weight, glucose-tolerant women age-matched to the obese women.

Global analysis of DNA methylation status in skeletal muscle biopsy specimens from the female patients indicated that methylation of so-called CpG and non-CpG sites did not differ between patients and controls, either before or after bariatric surgery.

But a separate genome-wide methylation analysis carried out in the six obese male patients undergoing bypass procedures, using a different chemistry and focusing on methylation of CpG sites, did reveal major changes between baseline and post-surgery follow-up.

It identified 409 differentially methylated regions, almost all of which showed reduced methylation after surgery. Some of these were near known protein-coding sequences, but most were in the vicinity of noncoding transcription start sites, the researchers indicated. This finding suggested "a possible contribution in initiation of transcription," they wrote.

The researchers also examined methylation at specific genes, expression of which was found to be different in patients versus controls at pre-surgery baseline, which showed marked differences between obese and healthy patients at baseline as well as between baseline and follow-up in the patient group.

A genome-wide analysis pointed to 896 genes with differential expression. At 6-month follow-up, "the expression of the majority of the identified genes was normalized to levels observed in the normal-weight, healthy women," Zierath and colleagues reported.

They then examined promoter methylation status at CpG sites in 14 of the genes. Eleven of those showed changes pre- and post-surgery, including eight with inverse correlations between methylation and expression and three with positive associations.

In addition, the researchers took an even closer look at two specific genes, PGC-1-alpha and PDK4, both of which help regulate mitochondrial activity and energy use in skeletal muscle.

Methylation of these genes, too, were abnormal in patients relative to controls at baseline, and were normalized with weight loss.

Limitations to the study included different methods used in the studies of male versus female patients, making it impossible to tell whether the results reflected genuine sex difference or assay-specific results.

Also, with follow-up data collected only at the single time point 6 months after surgery, Zierath and colleagues could not distinguish contributions from the surgery itself from those of weight loss. Previous studies have documented an antidiabetic effect of bariatric surgery within days of the procedure, long before any weight loss has occurred.

The study was supported by the Strategic Diabetes Program at Karolinska Institutet, The European Foundation for the Study of Diabetes, European Research Council Ideas Program, European Molecular Biology Organization, Swedish Research Council, Swedish Diabetes Association, Strategic ResearchFoundation, Knut and Alice Wallenberg Foundation, Stockholm County Council, and Novo Nordisk Research Foundation.

The authors declared no conflicts of interest.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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